ABSTRACT Opioid illegal use and misuse are producing extremely costly sequelae (e.g. overdoses, ED visits, deaths) at unprecedented levels. FDA-approved medications for treating opioid use disorder are effective, but there is a significant unmet need for alternatives especially relapse prevention. NIDA and the FDA have encouraged investigators to expand the range of therapeutic outcomes, beyond measurement of abstinence. Insomnia is a clinically significant, but understudied, correlate/predictor of relapse to substance use. Yet, most medications for treating insomnia have limited efficacy and can produce side effects. The orexin (OX) system plays a key role in sleep and substance use, offering a promising avenue for study. The dual OX-1/2 receptor antagonist suvorexant is an FDA-approved insomnia treatment, but it is unknown whether dual OX antagonism can improve opioid (or other substance) abstinence. This project will address whether OX-1/2 antagonism is a mechanism that can directly improve outpatient opioid abstinence (i.e. independent of opioid detoxification-related sleep disturbance), or whether OX antagonism corrects sleep deficiencies and indirectly improves opioid abstinence. Specific Aims are to determine whether nightly treatment with the OX-1/2 antagonist suvorexant (20 or 40 mg/day PO), relative to placebo: 1. increases outpatient opioid abstinence; and 2. improves sleep efficiency (time sleeping time in bed) on the residential detoxification unit. We will also determine 3. whether improved sleep efficiency predicts greater opioid abstinence (regardless of group assignment). Medication treatment will start on a residential detoxification unit (where sleep efficiency will be evaluated). Participants will be discharged and prospectively followed 13 weeks to evaluate opioid abstinence (assessed weekly via urinalysis and timeline followback self- report). Secondary outcomes include: retention; time to relapse; percent REM sleep; biomarkers of circadian rhythm, SNS and HPA axis function; medication adherence and satisfaction; actigraphy, daytime sleepiness; opioid craving and withdrawal symptoms; depression and anxiety symptoms; non-opioid substance use; global clinical severity, and health status. We will monitor safety including overdose, ED visits, and treatment readmissions. Impact of this project will be exceptional because: (1) opioid use problems remain at critically high levels yet detoxification-related sleep disturbance may increase (or predict) relapse risk; (2) our approach uses very rigorous methods (placebo controlled, dose-response, novel biomarkers, prospective abstinence/relapse assessment) and by systematically examining mediators/moderators of relapse (focusing on sleep efficiency but considering other factors), we will bridge a large translational gap; and (3) our findings could identify a novel and important therapeutic mechanism for the OX system in sleep and substance use/relapse. This project offers a template for investigating the effects of OX antagonists on drug relapse and biomarkers, and for developing therapeutic approaches to address this major public health problem. This highly innovative project should thus have an exceptionally strong and enduring impact on the field.